A new 12-membered, polymorphic gene family has recently been identified in Treponema pallidum, the causative agent of syphilis. The encoded proteins have predicted homology to the major sheath protein (msp) of T. denticola, and are characterized by variable and conserved domains. Our preliminary studies demonstrate that the msp-homologues serve as targets of opsonic antibody and induce significant immune protection, consistent with surface exposure. The overall goal of this project is to determine the nature and function of the immune response to the msp-homologues during syphilis and to examine the role of immunity in modulating msp-homologue expression. The following aims are proposed: 1) Define the humoral and cellular immune responses to individual msp variable and conserved domains during infection with T. pallidum to determine whether msp specificities are recognized over time, suggesting antigenic variation. 2). Determine the function of antibodies directed against the msp-homologue variable and constant regions of T. pallidum, Nichols strain in terms of opsonization, neutralization and immobilization. 3.) Determine the diversity of msp- homologue expression in T. pallidum-infected population. 4.) Investigate the ability of the immune response to modulate the expression of individual msp-homologues in T. pallidum to determine the role of role of immunity in msp-homologue expression. These studies will provide significant insights into the mechanisms by which T. pallidum causes multiple stages of disease and persists in the host for decades.